Heterologous prime-boost regimens are effective strategies to promote long-term memory and strong cellular Th1 responses to Mycobacterium tuberculosis , when BCG is used in the priming step. Subcutaneous or intranasal boosting of BCG-vaccinated newborn mice with native heparin-binding haemagglutinin (nHBHA) significantly enhances protection against M. tuberculosis. However, nHBHA is characterized by a complex methylation pattern in its C-terminal domain, which is important for protective immunogenicity in primary vaccination. In this study we addressed the question whether boosting with recombinant, non-methylated HBHA (rHBHA) produced in Escherichia coli may enhance protection of BCG-primed newborn mice. We found that while subcutaneous rHBHA boosting enhanced protection of BCG-primed mice against intranasal M. tuberculosis infection both in spleen and lungs, enhanced protection against aerosol infection was only seen in the spleen (0.72 logs; P < 0.05) but not in the lungs. Thus, in BCG-primed mice the methylation of the C-terminal domain of HBHA is dispensable for the induction of enhanced protection in the lungs against intranasal but not aerosol infection, whereas it enhances protection in the spleen in both challenge models. This report thus provides evidence that rHBHA may be considered as a booster vaccine against disseminated tuberculosis.
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机译：当在启动步骤中使用BCG时，异源的初免-加强疗法是提高长期记忆和对结核分枝杆菌强烈的细胞Th1反应的有效策略。用天然肝素结合血凝素（nHBHA）对接种了卡介苗的新生小鼠进行皮下或鼻内加强治疗可显着增强对结核分枝杆菌的保护作用。但是，nHBHA的特征是在其C末端结构域具有复杂的甲基化模式，这对于初次接种疫苗时的保护性免疫原性很重要。在这项研究中，我们解决了用大肠杆菌生产的重组非甲基化HBHA（rHBHA）加强免疫能否增强对BCG初生小鼠的保护的问题。我们发现，尽管皮下注射rHBHA可以增强BCG引发的小鼠在脾脏和肺中对鼻内结核分枝杆菌感染的保护作用，但仅在脾脏中可见对气溶胶感染的保护作用（0.72 log; P <0.05），而在肺中却没有。因此，在BCG引发的小鼠中，HBHA的C末端结构域的甲基化对于诱导增强的针对鼻内但不是气溶胶感染的肺保护是不可缺少的，而在两种挑战模型中，脾脏中的保护作用都得到增强。因此，该报告提供了证据，表明rHBHA可以被认为是抗结核传播的加强疫苗。
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